Phenylcyclopropane carboxylic acids and esters



United States Patent 3,313,842 PHENYLCYCLOPROPANE CARBOXYLIC ACIDS AND ESTERS Carl Kaiser, Haddon Heights, N.J., and Charles L. Zirkle,

Berwyn, Pa., assignors to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed May 16, 1963, Ser. No. 281,037 6 Claims. (Cl. 260-471) This invention relates to novel organic compounds and to processes for their preparation. In particular the present invention pertains to a new class of amino acids which find value as both therapeutic agents and as intermediates for the synthesis of new chemical substances.

The compounds of the present invention may be represented as follows:

R2 R1 OOOH wherein each of R R and R is hydrogen, hydroxyl, lower alkyl, lower alkoxy, benzyloxy, chloro, fluoro, bromo or trifluoromethyl.

As the above compounds contain both an amino function and a carboxylic function, it will be appreciated that these compounds can exist as a zwitterion. In addition, the formation of salts involving either the amino group or the carboxylic acid group of these dipolar molecules is possible by respective use of acids having a pKa below that of the carboxylic acid group, eg. hydrochloride, hydrobromide, sulfate, etc. or bases having a pKa above that of the amino groups, e.g. sodium, potassium, calcium, etc. While the compounds of this invention are herein depicted by Formula I above, it is to be appreciated that the full inventive concept embraces the various ionized forms thereof as well.

Since these molecules are asymmetric and may further exist in either the cis or trans configuration, four different isomeric forms are possible. Thus the present invention embraces both the dand l-cis isomers and the dand ltrans isomers. The cis and trans forms are prepared by different chemical syntheses while the dand l-isomersof either the cis or trans forms can be resolved by the classical methods, as for example, by formation of diastereoisomers.

The compounds of this invention serve as valuable intermediates in organic preparations representing synthetic amino acids which may for example be employed in the synthesis of new polypeptides or substituted for natural amino acids such as phenylalanine or tyrosine in the synthesis of modified protein molecules.

Furthermore, the compounds of the instant invention demonstrate hypotensive activity and are therefore useful in the treatment of various hypertensive conditions. While the mechanisms of such activity is by no means clear, it appears that it may be a manifestation of catecholamine release and depletion. When employed in this respect the compounds ofthis invention may be administered by any of the usual routes, especially oral, in a suitable pharmaceutical form such as tablets, capsules, sustained release preparations, solutions, suspensions or the like.

The process employed for the preparation of these compounds employs the selective hydrolysis of an appro- 3,313,842 Patented Apr. 11, 1967 priately substituted or unsubstituted phenylcyclopropanedicarboxylic acid ester of the formula:

R1 R1 /COOB ono on, o 0 0 B 3 wherein B represents a lower alkyl or similar protective group. The resulting monoester is then treated in one of two ways depending upon whether the cis or trans final product is desired. When the trans (phenyl to carboxyl) configuration is desired, the monoester (III) in the form of an alkali metal salt, e.g. sodium or potassium, is-treated .with hydrazine to form the corresponding hydrazide (IV). Treatment with nitrous acid then produces the corresponding acid azide (V) which upon heating loses nitrogen to yield the anhydride (VI). Hydrolysis then yields the desired trans amino acid (I). These reactions may be represented as follows:

R2 R1 COOB H OH: O O OK+ (III) R1 CONHNHn HONO . Ra N R2 R1 C QB 1 H/ Gfia \N=G=O a H O H2304 R: R! o o o B 7 H CH2 NHa R1 R1 C 0 0H H CH2 NH, s

(1 cis) The requisite phenylcyclopropanedicarboxylic acid monoester is prepared according to our invention by treatment of a dialkyl benzalmalonate (XI) with trimethylsulfoxonium iodide and strong alkali, e.g. sodium hydride, to yield the corresponding dialkyl phenylcyclopropanedicarboxylate (XII). Selective saponification with one mole of potassium hydroxide then yields the monoester potassium carboxylate (III).

R1 R COOB The following examples will serve to furthertypify the nature of this invention but should not be construed as a limitation thereof.

EXAMPLE -1 A solution of 106 g. (1 mole) of benzaldehyde, 176 g. (1.1 mole) of diethyl malonate, 10 m1. of piperidine and 10 g. of 'benzoic acid is refluxed azeotropically for five hours. The solution is cooled, washed three times with dilute hydrochloric acid, twice with aqueous sodium bicarbonate and twice with water, dried over magnesium sulfate and concentrated to an oil. This material is then distilled at 2 mm.-pressure to yield diethyl benzalmalonate as a colorless liquid.

To a suspension of 242 g. (1.1 mole) of trimethyl sulfoxonium iodide in 500 ml. dimethyl sulfoxide are added in several portions, 49.5 g. (1.1 mole) of a 53.3% dispersion of sodium hydride in mineral oil. The temperature is maintained at about by occasional cooling. Diethyl benzalmalonate (231 g., 0.93 mole) is then added dropwise over a one hour period while maintaining the temperature at 35 or below. The mixture is then stirred at 50 for one hour and poured into an excess of ice water and extracted twice with ethyl ether. The ethereal solution is washed with water, dried over magnesium sulfate and concentrated to an oil. The oil is taken up in 200 ml. of acetonitrile and the mixture then extracted twice with petroleum ether. The acetonitrile solution is dried over magnesium sulfate and concentrated to yield a pale yellow oil. This oil is then distilled in vacuo to yield diethyl Z-phenylcyclopropane-l,l-dicarboxylate, B.P. 141- 145 0.7 mm.

To a solution of 65.5 g. (0.25 mole) of diethyl 2-phenylcyclopropane-l,l-dicarboxylate in 200 ml. #30 alcohol is added a solution of 15 g. (0.27 mole) of potassium hydroxide in 30 ml. of water. The resulting mixture is allowed to stand at room temperature overnight and at the end of this time, refluxed for one hour. The alcohol is removed in vacuo and the residue refluxed azeotropical- 1y with benzene after which the benzene is removed in vacuo. The residue is next dissolved in 200 ml. of #30 alcohol and 1.5 l. of ethyl ether is then added. After cooling, the white crystalline solid is collected by filtration and dried to yield a hydrated potassium salt of ethyl l-carboxy-2-phenylcyclopropanecarboxylate. This material, demonstrating a melting point of 131 (dec.), is then dissolved in 100 ml. of water and acidified with dilute hydrochloric acid. The solid which forms upon cooling is collected by filtration and dried to give ethyl l-carboxy- 2phenylcyclopropanecarboxylate, M.P. 59-63 EXAMPLE 2 A mixture of 13.6 g. (0.05 mole) of ethyl potassium 2-phenylcyclopropane-l,l-dicarboxylate, 35 ml. of #30 alcohol and 100 ml. of hydrazine hydrate is heated on a steam bath for four hours and then concentrated in vacuo. The residue is stripped twice with dry toluene and dissolved in m1. of water and 100 ml. of ethyl ether and treated with 2.4 g. (0.034 mole) of sodium nitrite. Twenty-five milliliters of concentrated hydrochloric acid are then added dropwise while maintaining a temperature below 0. The layers are separated and the aqueous layer extracted with ethyl ether. The com bined ethyl ether fractions are dried over magnesium sulfate and concentrated below 20 to yield an oil. This oil is dissolved in 100 ml. of dry toluene and heated cautiously on steam bath until nitrogen evolution is complete. This material is then concentrated in vacuo to an oil which is stirred for two minutes with 25 ml. of 10% sodium hydroxide. The mixture is then extracted with ethyl ether. The aqueous layer is acidified with concentrated hydrochloric acid. The insoluble material is extracted with ethyl ether and the aqueous portion adjusted to pH 7. Upon cooling, the solid which forms is collected and washed successively with water, acetone and ether. The solid is collected and dried to give trans- 1amino-Z-phenylcyclopropanecarboxylic acid, MP. 179 180 (dec.). The amino acid is suspended in 25 ml. #30 alcohol and acidified with ethereal hydrochloric acid. The solution is filtered and ether is added to the filtrate. The white crystals which form are collected to yield trans- 1amino-2-phenylcyclopropanecarboxylic acid hydrochloride, M.P. 216-2l7 (dec.).

EXAMPLE 3 To a solution of 23.5 g. (0.1 mole) of ethyl l-carboxy- 2-phenylcyclopropanecarboxylate (prepared as in Example 1) in ml. of acetone at 0 are added dropwise 20 g. of triethylamine. Twenty-five grams of ethyl chlorocarbonate in 50 ml. of acetone are then added dropwise followed by a solution of 25 g. of sodium azide in 60 ml. of water, maintaining a temperature below 0 C. The mixture is stirred at 5 for 30 minutes and then poured into 1 l. of ice Water and extracted three times with toluene. These extracts are dried over magnesium sulfate and then heated cautiously on a steam bath until nitrogen evolution is complete. The solution is then concentrated in vacuo to yield the yellow oily isocyanate ester.

The isocyanate ester (5.0 g.) is added to a freshly prepared solution of ml. of concentrated sulfuric acid and 25 ml. of water and stirred at 6070 for about minutes. Any insoluble material is removed by filtration and the filtrate cooled to give an ethyl l-amino-Z-phenylcyclopropanecarboxylate as the sulfate. This salt is dissolved in 15 ml. of #30 alcohol and an excess of 10% aqueous sodium hydroxide is added. The solution is heated on a steam bath for thirty minutes during which time the alcohol is allowed to evaporate. The alkaline solution is then adjusted to pH 7 with acetic acid and the crystals which form collected by filtration and suspended in ethyl alcohol. This suspension is adjusted to pH 2 with alcoholic hydrochloric acid and filtered. The filtrate is flooded with ethyl ether to yield cis-1-amino-2- phenylcyclopropanecarboxylic acid hydrochloride, melting point for the hydrated product 224 (dec.). This hydrochloride is dissolved in water and the pH adjusted to 7 with aqueous sodium hydroxide. The solid thus formed is collected to give the free amino acid, cis-lamino-2-phenylcyclopropanecarboxylic acid, M.P. 223 (dec.).

EXAMPLE 4 The following aldehydes are substituted in equivalent amounts of benzaldehyde in the procedure of Example 1:

p-tolualdehyde 3,5 -dimethylbenzaldehyde 2,4,6-trimethylbenzaldehyde p-chlorobenzaldehyde m-fluorobenzaldehyde p-bromobenzaldehyde p-trifiuoromethylbenzaldehyde m-methoxybenzaldehyde 3,4-diethoxybenzaldehyde 3,4-dimethoxybenzaldehyde Upon completion of the steps therein described, the

following compounds are respectively obtained:

ethyl 1-carboxy-2-(4-methylphenyl)cyclopropanecarboxylate ethyl l-carboxy-Z-(3,5-dimethylphenyl)cyclopropanecarboxylate ethyl l-carboxy-2-(2,4,6-trimethylphenyl)-cyclopropanecarboxylate ethyl 1-carboxy-2- (4-chlorophenyl cyclopropanecarbox- These monoethyl esters are then subjected to the reactions of Example 3 to obtain the cis isomers of the following compounds while the potassium salts of the above esters are subjected to the reactions of Example 2 to obtain the trans isomers of the following compounds:

1-amino-2-(4-methylphenyl)cyclopropanecarboxylic acid 1-amino-2- 3 ,5 -dimethylphenyl cycloprop anecarboxylic acid 1-amino-2-(2,4,6-trimethylphenyl) cyclopropanecarboxylic acid l-amino-Z-(4-chlorophenyl) cyclopropanecarboxylic acid 1-amino-2-(3-fluorophenyl)cyclopropanecarboxylic acid 1-amino-2-(4-bromophenyl) cyclopropanecarboxylic acid 6 1-amino-2-(4-trifluoromethylphenyl)cyclopropanecarboxylic acid 1-a;mino-2-( 3 -methoxyphenyl) cycloprop anecarboxylic acid 1-amino-2-(3,4-diethoxyphenyl)cyclopropanecarboxylic acid l-amino-Z- (3,4-dimethoxypheny1) cycloprop anecarboxylic acid EXAMPLE 5 By employing 3-benzyloxybenzaldehyde in the procedure of Example 1 and the resulting ethyl l-carboxy- 2 (3-benzyloxyphenyl)cyclopropanecarboxylate in the procedure of Example 3, there is obtained cis-l-amino- 2-(3-benzyloxyphenyl)cyclopropanecarboxylic acid, M.P. 221 C. as the hydrochloride.

To a suspension of 0.5 g. of this material in 25 ml. of glacial acetic acid are added 15 ml. of concentrated hydrochloric acid. The solution is heated at steam bath temperature for thirty minutes before the introduction of an additional 10 ml. of concentrated hydrochloric acid with heating for another thirty minutes. The mixture is then concentrated in vacuo and the residue dissolved in ethanol. The pH is adjusted to 8.0 by the addition of triethylamine. The solid is collected by filtration and washed with ethanol and ethyl ether to yield cis-1-amino-2-(3 hydroxyphenyl) cyclopropanecarboxylic acid which after recrystallization from a small amount of water, demonstrates a melting point of 226-227 (dec.)

The corresponding trans isomer of 1-amino-2-(3-hydroxyphenyl)cyclopropanecarboxylic acid is obtained by subjecting the potassium salt of ethyl 1-carboxy-2-(3- benzyloxyphenyl)cyclopropanecarboxylate to the procedure of Example 2 followed by treatment with hydrochloric acid an acetic acid as described in this example.

EXAMPLE 6 This cis and trans isomers of 1-amino-2-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid are obtained in an analogous fashion to that described in Example 5. By employing 3,4-dibenzyloxybenzaldehyde in the procedure of Example 1, there is obtained ethyl l-carboxy- 2- 3,4-dibenzyloxyphenyl) cyclopropanecarboxylate. By following the procedures of Examples 3 and 5, this compound is converted into the cis-1-amino-2-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid whereas by fo1lowing the procedures of Examples 2 and 5 the corresponding trans isomer of l-amino-2-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid is obtained.

What is claimed is:

1. A compound selected from the group consisting of amino acids of the formula:

R2 R1 COOH wherein each of R R and R is a member selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, ethoxy, chloro, bromo, fluoro, trifluoromethyl and benzyloxy and the pharmaceuticallyacceptable acid addition and alkali salts thereof.

2. A compound of the formula:

3. A compound of the formula:

4. A compound of the formula:

5. A compound of the formula:

COOH

COOH

COOB

COOB' 8 wherein each of R R and R is a member selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, chloro, bromo, fiuoro, trifluoromethyl and 5 benzyloxy, and

each of B and B is a member selected from the group consisting of hydrogen and lower alkyl.

References Cited by the Examiner UNITED STATES PATENTS 8/1962 Burger 260-515 12/1962 Kaiser et a1. 260--515 LORRAINE A. WEINBERGER, Primary Examiner. 15 D. D. HORWITZ, Examiner.

A. THAXTON, Assistant Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF AMINO ACID OF THE FORMULA: 